Science Pool

The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent

This publication details the discovery of a series of selective agonists for Transient Receptor Potential Melastatin 5 (TRPM5) culminating with the identification of a lead compound.

Gastrointestinal (GI) disease including inflammatory bowel disease (ulcerative colitis and Crohn’s disease), and GI motility disorders (neuropathic constipation (NC), and gastroparesis) are serious life limiting conditions for patients. TRPM5 is a non-selective monovalent cation channel activated by intracellular Ca2+ increase which, within the GI system, plays a critical role of propagating the signal through membrane depolarization and initiating the release of Interleukin (IL)-25 and other paracrine factors. We hypothesized that a TRPM5 agonist will activate the release of IL-25 and non-neuronal ACh, leading to improvement in motility through a prokinetic mechanism.

In the paper we describe: 

• The process of our discovery starting from a high throughput screening hit through to the identification of a lead compound
• The selectivity of the lead compound versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8
• The drug metabolism and pharmacokinetics (DMPK) profile of the lead compound
• The in vivo efficacy of lead compound in a mouse model of gastrointestinal motility

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Thermostability assays (DSF) are one of the workhorses of biochemistry and structural biology. Thanks to the simplicity of the assay setup they found wide applications in many fields. To meet the high demand in DSF assays from our clients, Evotec established DSF pipelines in all five of the sites that offer biophysics services. We find that thermostability assays are highly useful for hit validation & expansion, however, can be also used to reveal the mode of action of the candidate molecule.

In this presentation we:

• Describe how we use thermal unfolding assays (DSF) to support drug discovery
• Discuss the cases when model-based analysis reveals in-depth information about the drug/target interaction
• Share the perspectives on combing high-throughput and high-content approaches

Volume 1 of Evotec's DDxp (Drug Discovery Expertise) series focuses on Rare Diseases, looking particularly at Gene Therapy and Huntington's Disease. The articles are written by our in house experts and also feature Sarah Winckless, an Olympic and World Champion rowing medallist, who documents her own experience with Huntington's Disease.

Download it now to find out more.

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Chinook Therapeutics and Evotec joined forces for a patient-centric target identification supported by strong translational evidence to initiate drug discovery programs with a focus on tubular failed repair and cross-talk in the tubulointerstitial niche.

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Date: 23-24 November, 2022

Venue: ENS Lyon, France

Attendees: Sebastien Coyne (Group Leader In Vitro Biology ID), Francesca Bernardini (VP In Vitro Biology & AMR Lead), Antoine Alam (VP Head of Virology), Lilia Boucinha (Team Leader, Global Bioinformatics), Christelle Dagoneau (SVP Business Development) Nadir Bessila (Business Development Executive) and Florian Marro (Research Associate, Mass Spectrometry & Phenomics)

Evotec will be sponsoring this year’s I4ID conference as well as showcasing its research on-site in Lyon.

Oral Presentation: Leveraging Continuous Manufacturing to Expand Global Access to Biotherapeutics - Presentation by Christelle Dagoneau

During this session, Christelle will present a unique platform concept that integrates the discovery, development, and manufacture of biologics in innovative and easily deployable production facilities called J.POD. She will particularly describe how the Just-Evotec Biologics cutting-edge AI/ML protein design technologies combined with industry-leading intensified continuous bioprocess can help de-risk and accelerate biotherapeutics development from lead generation through to BLA while offering cost-effective and truly flexible clinical and commercial supply solutions.

Oral Presentation: Alternative Approach to Discover Small Molecule Antibiotics - Presentation by Sebastien Coyne

Discovering new antibacterial drugs is urgently needed but represents many challenges. Alternative approaches to discover such new drugs are currently being explored and might offer a promising solution. We present one alternative approach that consists of screening for antibacterial drugs in in vivo mimetic medium. These culture conditions, defined to better reflect the conditions a bacterium would face at an infection site, allowed to discover active small molecules with new mode of action and/or representing novel chemical matter.

Poster Presentation by Florian Marro: Intracellular Staphylococcus aureus replicative dynamics monitoring under antibiotics challenges: highlighting persiste

If you wish to meet with us in Lyon, get in touch via the form below, we will be happy to arrange a meeting.

Learn more about the 6th I4ID congress

At Evotec we are committed to the development and usage of new technologies. With the objective to stay at the cutting edge of science and propose innovative solutions, several working groups have been created and are actively involved in various fields: photochemistry, electrochemistry, flow chemistry, biocatalysis... As part of this strategy, the working group “green chemistry” aims to design chemical products and processes that reduce or eliminate the use or generation of hazardous substances. We are always looking for safer, greener and cleaner methodologies to reduce the environmental impact of our activities and adopt the green chemistry principles¹. Green chemistry applies across the life cycle of a chemical product, including its design, manufacture, use, and disposal. Moreover, we are also engaged in energy saving to decrease the global carbon footprint of the company. Sustainability and green chemistry are implemented while maintaining our level of excellence in drug discovery. To reach our objectives, we have identified four areas of improvements:

This poster is focused on two areas in continuous improvement at Evotec: solvent alternatives and energy saving. Some examples of reactions carried out in renewable solvents such as MeTHF² and DMI³ are presented. Alternatives to DCM (potential ozone depletory and suspected carcinogenic solvent) usage for work-up and purification are also shown⁴.

The poster was presented by Kim Spielmann at the Journées de Chimie Organique held on 2-4 November 2022 at the École Polytechnique, Palaiseau, France.

¹Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, 30, By permission of Oxford University Press
² a) Coby J. Clarke, Wei-Chien Tu, Oliver Levers, Andreas Bröhl, and Jason P. Hallett Chemical Reviews 2018, 118, 747 b) Pace, V., Hoyos, P., Castoldi, L., Domínguez de María, P. and Alcántara, A.R. ChemSusChem 2012, 5, 1369 c) Andrew Jordan, Callum G. J. Hall, Lee R. Thorp, and Helen F. Sneddon Chemical Reviews 2022, 122, 6749
³ a) Aricò, F.; Tundo, P. Beilstein J. Org. Chem. 2016, 12, 2256 b) F. Aricò, A. S. Aldoshin, P. Tundo, ChemSusChem 2017, 10, 53 c) Russo F., Galiano F., Pedace F., Aricò F., and Figoli A. CS Sustainable Chem. Eng. 2020, 8, 1, 659
⁴ a) Peterson E.A., Dillon B., Raheem I., Richardson P., Richter D., Schmidte R. and Sneddon H.F. Green Chem., 2014,16, 4060 b) Taygerly J.P., Miller L.M., Yeec A. and Peterson E.A. Green Chem., 2012,14, 3020 c) MacMillan D.S., Murray J., Sneddon H.F., Jamiesona C. and Watson A.J.B. Green Chem., 2012,14, 3016

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Our factsheet gives an overview of Evotec Modena's capabilities. Download it now to discover more.

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Date: 05th December, 2022 

Location: Takeda Pharmaceuticals Company 35 Lansdowne street, Cambridge, MA 02139

Attendees: Ralf Geiben Lynn, Chris Strock, Sravani Adusumalli, Anu Marahatta & Li LI

Learn about 2022 NEDMDG Winter Meeting

Date: 29 November - 2 December 2022

Location: Burleigh Court, Loughborough, UK

Attendee: Ben Smith

Learn more about DMDG Large Molecules course

The 13^th edition of our Drug Discovery Update (DDup) provides insights into our unique PanHunter next generation multi-omics data analysis platform.

In this edition, it covers:

• an introduction to PanHunter and multi-omics data analysis including:
  • the importance of multi-omics data (genomics, transcriptomics, proteomics and metabolomics) in understanding the complexity of disease and treatments
  • how the versatile and interactive multi-omics analysis platform, PanHunter, can greatly simplify the data analysis and interpretation process and so reduce time, improve visualisation and contextualisation, and inform decisions
  • how PanHunter can access additional meta information, reference data, chemical and structural information and clinical data to  provide further relevance and perspective

• an interview with Dr John Szilagyi at Bristol Myers Squibb on how he uses PanHunter and the benefits it brings
• a case study on how PanHunter has been applied in rapid candidate biomarker discovery
• user perspectives from different functions within Evotec (wet lab biologists, computational biologists and bioinformaticians) on how PanHunter is making an impact on their research

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